The whole diet, the combination of foods and beverages, is important in the prevention and treatment of coronary heart disease (CHD). Dietary intake is a life-long environmental factor indispensable for humans. Although the gene-environment interaction is pivotal in CHD, it is not completely known how the whole diet regulates gene expression, and whether such regulation is a mechanistic link between the whole diet and CHD. MicroRNAs (miRs) regulate gene expression post-transcriptionally. Dietary patterns have been used to evaluate the whole diet. In our pilot studies, we demonstrated that miRs were associated with a healthy whole diet pattern, ?modified Mediterranean diet (mMedDiet) pattern?, and were prospectively associated with CHD. Thus, our overall objective is to prospectively investigate dietary modulation of miRs and CHD for better understanding of dietary regulation of gene expression and its relation to CHD in the large cohort. Our preliminary data showed that a mMedDiet pattern was prospectively associated with low CHD risk in a well- characterized community cohort, the Atherosclerosis Risk in Communities Study (ARIC). Similarly, our published data showed that a mMedDiet pattern was prospectively related to lower subclinical atherosclerosis in a well-characterized, multi-ethnic cohort, the Multi-Ethnic Study of Atherosclerosis (MESA). Therefore, we propose a two-phase, individually matched case-control (1:2) study nested in both ARIC and MESA cohorts. Matching on age, sex, race, field center, calendar date for plasma collection, and freeze/thawing cycle, using risk-set sampling, we will include 412 incident CHD cases and 824 risk-set matched controls from ARIC (phase 1 for next-generation sequencing based miR measures) and for phase 2, replication ? 361 incident CHD cases and 722 risk-set matched controls from MESA. To capture the complex nature of the whole diet and numerous synergies and antagonism among food items (including nutrients, food components, and substances such as additives and preservatives), we will use multiple healthy dietary patterns. Systemic miRs will be profiled in plasma using the state-of-the art small RNA-seq in ARIC, and candidate and screened miRs will be measured using qPCR in ARIC and MESA. We aim to determine cost-efficiently: 1) whether the whole diet represented by healthy dietary patterns, is prospectively associated with miRs; and 2) whether pre-diagnosis miRs that are prospectively related to incident CHD are associated with whole diet. We will identify diet-related and CHD-related miRs from candidate miRs and other miRs. We will further assess to what extent miRs explain the difference in CHD risk between participants with higher diet scores and those with lower diet scores. Findings from our study will shed light on miRs as a novel pathway linking whole diet to CHD event, and will provide insight into the use of miRs as novel biomarkers for dietary regulation of genes and as proxies to evaluate new therapeutic approaches and public health strategies to prevent CHD events.